Abstract
BackgroundDNA methylation plays an important role in regulating gene expression during many biological processes. However, the mechanism of DNA-methylation-dependent gene regulation is not fully understood. Here, we explore two possible DNA methylation regulatory mechanisms with opposite modes of gene expression regulation.ResultsBy comparing the genome-wide methylation and expression patterns in different tissues, we find that majority of tissue-specific differentially methylated regions (T-DMRs) are negatively correlated with expression of their associated genes (negative T-DMRs), consistent with the classical dogma that DNA methylation suppresses gene expression; however, a significant portion of T-DMRs are positively correlated with gene expression (positive T-DMRs). We observe that the positive T-DMRs have similar genomic location as negative T-DMRs, except that the positive T-DMRs are more enriched in the promoter regions. Both positive and negative T-DMRs are enriched in DNase I hypersensitivity sites (DHSs), suggesting that both are likely to be functional. The CpG sites of both positive and negative T-DMRs are also more evolutionarily conserved than the genomic background. Interestingly, the putative target genes of the positive T-DMR are enriched for negative regulators such as transcriptional repressors, suggesting a novel mode of indirect DNA methylation inhibition of expression through transcriptional repressors. Likewise, two distinct sets of DNA sequence motifs exist for positive and negative T-DMRs, suggesting that two distinct sets of transcription factors (TFs) are involved in positive and negative regulation mediated by DNA methylation.ConclusionsWe find both negative and positive association between T-DMRs and gene expression, which implies the existence of two different mechanisms of DNA methylation-dependent gene regulation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1271-4) contains supplementary material, which is available to authorized users.
Highlights
DNA methylation plays an important role in regulating gene expression during many biological processes
We find that the T-Differentially methylated region (DMR) that are positively correlated with gene expression are likely to be functional and that the genes associated with these Tissue-specific differentially methylated region (T-DMR) are enriched for those that negatively regulate transcription and metabolism, suggesting a novel, two-layer mechanism of DNA methylationdependent gene regulation
A significant number of T-DMRs positively correlate with gene expression In our previous genome-wide profiling of DNA methylation profiles of mouse retina and brain [11], we identified 2498 T-DMRs
Summary
DNA methylation plays an important role in regulating gene expression during many biological processes. The mechanism of DNA-methylation-dependent gene regulation is not fully understood. We explore two possible DNA methylation regulatory mechanisms with opposite modes of gene expression regulation. DNA methylation regulates many biological processes, including development and disease by modulation of gene expression. The methylation of a significant fraction of DNA methylation sites are positively correlated with gene expression [10], challenging the traditional view that DNA methylation represses gene expression. For the methylation sites that are positively correlated with gene expression, many questions remain to be answered. Are these methylation sites functional? Do they preferentially regulate downstream genes with certain gene functions? Do they interact with different TFs?
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